Pancreatic Cancer Progress:
Fact or Fiction?
Eileen M. O’Reilly, M.D.
Associate Member
GI Medical Oncology
Memorial Sloan-Kettering Cancer Center
New York, NY
Ten Abstracts
• Adjuvant therapy
– RTOG 97-04 secondary endpoint analyses (2)
– New adjuvant combinations (1)
• Advanced Disease
– Front-line therapy (3)
– Second-line therapy (2)
• Newer Agents/ Targets
– TNFerade, Ras & EGFR (2)
Adjuvant Therapy
US Intergroup Adjuvant (RTOG 97-04)
Resected Pancreatic Cancer
(N= 538)
Gemcitabine
↓
5-FU infusion + RT
↓
Gemcitabine
5-FU infusion
↓
5-FU infusion + RT
↓
5-FU infusion
Regine, et al. (RTOG). ASCO, 2006
RTOG 97-04 Results (ASCO 2006)
Pancreatic Head Tumors (N= 380)
Gem Arm
5-FU Arm
Median Survival
20.6 mths
16.9 mths
3-Year Survival
31%
21%
HR 0.79 (CI 0.63- 0.99, p= 0.047)
No significant difference when body/tail tumors included
(N= 422, p= 0.013)
Regine, et al. ASCO, 2006
RTOG 97-04: Radiation QA & Outcome
Abrams, et al. Abst #4523
• Designated ‘per protocol (pp)’ or not
– For pp pts, OS 20.9 vs 17.6 mths, p= 0.019
• Multi-variate analysis: RT QA score enhanced
survival in all pts, panc head pts
• Key points
– Non-adherence to RT QA negatively impacts
survival
– RT QA score and toxicity correlation – not reported
– Volume per center did not correlate with survival*
Abrams, et al. Int J Rad Oncol, Biol, Phys, 2006*
RTOG 97-04: Post-Surgery Ca 19-9 Analysis
Berger, et al. Abst #4522
• Ca 19-9 – tumor associated antigen; expression
related to Lewis blood group antigens
• 7- 15% Lea-b-: non-detectable Ca 19-9
• Results (N= 365, 66 indeterminate)
– Independent prognostic factor for OS in all pts
<180 vs ≥180 U/ml, HR 3.58, p< 0.0001
– ≥180 U/ml – median survival ~9 months
<180 U/ml – median survival ~21 months
– Lea-b- (34%), similar to survival of Ca 19-9 <180
Adjuvant Phase II GemOx → Gem + RT
Mornex, et al. Abst #4520
•
•
•
•
•
Single-arm, multi-center, phase II
GemOx x 6 → Gem (weekly) + RT 50 Gy
N= 49
T1-2 49%, N0 57%
Primary endpoint
– 1-year recurrence-free survival: 71%
– Early toxicity: GI, myelosuppression
– Immature for OS, late toxicity analysis
Adjuvant Therapy
• No universal accepted standard approach
• Options include
– U.S: traditionally combined chemoradiation →
chemotherapy (RTOG 97-04)
– Europe: chemotherapy (ESPAC-1, CONKO-001)
– [Observation]
• No consensus on value of radiation therapy
Major Questions in Adjuvant Therapy
Pancreas Cancer 2007
1. Is gemcitabine superior to 5-fluorouracil?
2. Absolute value of radiation?
3. Value of additional agents in the adjuvant
setting – combination cytotoxics, ‘targeted’
agents?
ESPAC-3 v2
(accrued 12/06 Pancreas Cancer)
Resected Pancreatic Cancer
(N = 990)
Observation
5-Fluorouracil
Leucovorin
Gemcitabine
Primary Endpoint: Two-year survival
EORTC 40,013-22012 Phase II → III
(Phase II accrued 1/07)
Resected Pancreatic Cancer
(N= 78/ 538)
Gemcitabine
Gemcitabine
↓
Gemcitabine + RT
J Van Laethem (EORTC)
Adjuvant Therapy
What Have We Learnt Today?
• Post-op Ca 19-9 powerful predictor of survival
>180 U/ml – included in adjuvant studies?
stratify based on Ca 19-9
• Quality control of radiation is important
– Supports routine incorporation of RT QA
phase III trials
• Integration of new drugs in the adjuvant
setting is key
Advanced Pancreas Cancer
Front-Line Therapy
Gemcitabine + Drug Vs Gemcitabine?
Heinemann, et al. Abst #4515
HR
Survival
P-Value
N
Gem + platinum
0.85
0.01
623, 5 trials
Gem + 5-FU
0.90
0.03
901, 6 trials
Good PS 90%+
Poor PS 60- 80%
0.76
1.08
<0.0001 1,108, 5 trials
0.04
574
Rand. Phase II (→ III): FOLFIRINOX vs Gem
Ychou, et al. Abst. #4516
•
•
•
•
FOLFIRINOX – phase II, 26% RR, OS 9.5 mths*
Multi-center, two-stage design, randomized phase II
Primary endpoint: RR (phase II)
[Now accruing as phase III]
N
RR
G3-4
Neutropenia
G3-4
Fatigue
FOLFIRINOX
44
31.8%
88%
(2% febrile)
35%
Gemcitabine
44
11.4%
37%
35%
Conroy, et al. J Clin Oncol, 2005*
ECOG 8200: Rand. Phase II
Irinotecan + Docetaxel +/- Cetuximab
Burtness, et al. Abst #4519
• ECOG 0-1
• Primary endpoint: RR (two-stage design)
• Low molecular weight heparin prophylaxis
N
RR*
PFS
OS
ArmA: I+D
43
2.3%
2.8 mths
6.5 mths
ArmB: I+D+C
43
7%
4.5 mths
5.3 mths
Inevaluable for primary endpoint: Arm A 18%; Arm B 30%
Pooled:
50%
Decline
Ca 19-9
OS byOS
50%Dropby
FromBaseline
CA19-9:
E8200 Pooled Data
1.0
0.9
Survival Probability
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
p=0.020
0.0
0
5
10
15
20
25
30
Overall Survival Time in Months
50% Drop in CA19-9
No
Yes
TOTAL
48
25
DEAD
42
22
ALIVE
6
3
MEDIAN
5.6
9.9
35
Significance of ECOG 8200
• No evidence of superiority of cetuximab arm
• Toxicity substantial in both arms
> 20% rates Gd 3-4 toxicities (ANC, diarrhea)
• New endpoint Ca 19-9 50% drop – better
surrogate for PFS, OS than RR?*
• LMWH prophylaxis as part of front-line therapy
(CONKO-004, FRAGEM trial)?
Wong, et al. Gastrointestinal Cancers Symposium, 2007 (Abst # 116)*
Combination Therapy –
Which Patients With Advanced PC?
• Themes consistent
– Good PS pts: gemcitabine + platinum or
fluoropyrimidine or erlotinib
– Poor PS pts: gemcitabine +/- erlotinib
– Large trials, meta-analyses to show benefit*
• Two-drug vs three-drug combinations?
– Benefit vs toxicity ratio unanswered
– Limited to good PS pts
• Non-gemcitabine combinations – possibly?
Xie, et al. W J Gastro, 2006*
Advanced Pancreas Cancer
Second-Line Therapy
CONKO-003
Phase III FU+FA+Ox vs FU+FA
Riess, et al. Abst #4517
• Primary endpoint: 2 month improvement in OS
• Secondary: TTP, RR, toxicity
N
FU+FA+Ox
FU+FA
76
89
TTP
OS
(N= 145)
(N= 130)
12.3 weeks
45 weeks
(10.9 – 123.7)
(40.5 – 49.5)
8 weeks
35.6 weeks
(6.4- 9.5)
(29.6 – 41.5)
p> 0.05
Second-Line Therapy
• Poorly studied & limited data
• Default – fluoropyrimidine-based therapy
• 40%+ of patients treated on recent phase III
trials receive 2nd-line therapy
• Most data retrospective e.g., G-FLIP, GTX
• Prospective mostly phase II data
• Opportunity for clinical trials
Selected 2nd-line Trials
RR
-
Survival
10.4 mths
8.3 mths
Author
Riess. ASCO, 2007
409
-
3.5 mths
3.1 mths
Papish. ASCO, 2005
30
30
30
41
52
22%
23%
10%
2%
4%
6 mths
~6 mths
23% 1-yr
22% 1-yr
~5 mths
Demols. BJC, 2006
Tsavaris. In New Drugs, 2005
Cantore. Oncology, 2004
Xiong. PASCO, 2006
Boeck. Ann Oncol, 2007
38
0%
16%
4.3 mths
6.5 mths
Ulrich-Pur. BJC, 2003
N
Phase III Trials
FU+LV+ Oxali (OFF) 130*
vs FU+ FA
Rubitecan
vs Dealers choice
Phase II Trials
Gem-Oxali
FU + LV + Oxali
CPT-11 + Oxali
Capecit + Oxali
Pemetrexed
Ralitrexed
vs Ralit + CPT-11
CALGB 80303: Second-Line Therapy
Schrag, et al. Abst #4524
• Analysis of post study treatment
• Key points
– < 50% receive a 2nd-line of treatment
– Older, low PS pts – lower likelihood of therapy
– 2% receive experimental therapy second-line
Second-Line Therapy
Conclusions
• A clear unmet niche in PC
• Data to support oxaliplatin 2nd-line therapy
• Challenges are
– Limited pt population eligible and well enough
for (experimental) therapy
– Limited pancreas cancer focused 2nd-line trials
co-operative group mechanism (CALGB
80603)
Novel Therapeutics
Phase II-III 5FU + RT +/- TNFerade (PαCT)
Posner, et al. Abst #4518
• TNFerade – adenoviral vector + RT promotor + transgene
human TNFα
• Phase I-II study: N= 50; MTD 4 x 1011 pu
• 10 endpoint (Phase III): 20% improvement in 1-yr survival
Randomized Phase III
Locally Advanced Pancreas Cancer
(N= 330)
5-FU + RT (5,040 cGy)
+/- TNFerade 2:1 randomization
↓
Gemcitabine +/- Erlotinib
TNFerade
• Interim analysis after N= 51 on phase III
– Treatment well tolerated – no imbalance in
SAE’s
– Accrual slow – endoscopic route now feasible
which should assist accrual
– Data are immature to comment on survival –
early ‘looks’ can be misleading
NCIC PA.3: K-ras, EGFR & Outcome
Moore, et al. Abst #4521
• N= 569; 146 adequate specimens (26%)
• N= 86, both EGFR (FISH), Ras data
K-Ras Mutant
K-Ras WT
HR
P
OS
6.7 mths
5.4 mths
0.63
0.37
PFS
3.8 mths
3.7 mths
0.86
0.53
EGFR (+)
EGFR (-)
OS
5.3 mths
7.8 mths
1.24
0.32
PFS
3.6 mths
4.2 mths
1.85
0.004
EGFR, Ras Correlation with Outcome?
• EGFR overexpression ~70-90% pancreas ca
• Predicts for advanced stage and decreased
survival
• NSCL, colorectal cancer
– EGFR copy # (FISH) associated with response
– EGFR (IHC) not associated with outcome
– Presence of K-ras mutations associated with
resistance, inferior outcomes
Molecular Therapy for PC
• PA.3 study no real hints at selectivity
– EGFR (-) better OS
– Trend for benefit to erlotinib in Ras-WT, HR 0.66;
EGFR (-), HR 0.6, for OS
• Rash – pharmacodynamic marker for
outcome, p< 0.001
• Tissue acquisition, biomarker data – a real
goal for future studies (~26% of pts in PA.3)
Progress – Fact or Fiction?
• Definitely (modest) progress
– Refinements in adjuvant therapy –
stratification for Ca 19-9, RT delivery
– Endorsement for selected gemcitabine-based
two-drug cytotoxic combinations front-line
– New second-line therapy for selected pts?
• Future – new drugs….